Parkinson's disease was first described in 1817, as a neurological disorder characterized by tremor, muscular rigidity, and loss of postural reflexes. It typically presents in middle age, and is a leading cause of neurological disability in individuals 60 and older. Current estimates are that 100-150 of every 100,000 people are afflicted with Parkinson's disease.
Early signs of the disease typically begin with relative immobility of facial expression, infrequent blinking, fixed trunk postures, and difficulty in sitting or rising. These signs are generally followed by symptoms of tremor, slowness and fatigue, loss of dexterity, disturbances in gait, psychological depression, and others. Later symptoms include muscular rigidity and difficulty in performing volitional motor activities. The patient may lose many reflex motions, such as eye blinking, automatic shifting of weight when standing or sitting, arm swinging while walking, which must be performed consciously. The course of Parkinson's disease is progressive, and causes severe disability or death in 25% of patients within 5 years of onset, in 65% of patients within 10 years, and in 80% of patients within 15 years.
Parkinson's disease is now associated with the gradual destruction of catecholamine neurons in the brain, particularly in the substantia nigra, locus ceruleus, and brain-stem nuclei. Dopamine concentration in the caudate nucleus, putamen, and pallidum is depleted, and is correlated with the degree of cell loss in the substantia nigra.
Current therapy is based on administration of L-DOPA, which is metabolized to dopamine in vivo. L-DOPA is often administered in combination with a peripheral decarboxylase inhibitor (e.g., carbidopa), which inhibits metabolism of dopamine, and thus reduces the amount of L-DOPA required. Others have administered monoamine oxidase (MAO) inhibitors such as deprenyl, which inhibits metabolism of dopamine by MAO, allowing the accumulation of dopamine and prolonging its action. However, L-DOPA treatment also presents a host of side effects, including involuntary movements, confusional states, and toxic psychosis. Tolerance for the drug typically develops over time, such that the dosage administered is gradually increased until contraindicated by side effects. The disease continues to progress.
Lately, a great deal of interest has arisen in the possible use of tissue transplant as a means to ameliorate the progression of the disease. See for example M. Herrera-Marschitz et al, Brain Res (1984) 297:53-61; E-O. Backlund et al, J Neurosurg (1985) 62:169-73; I. Stromberg et al, Exp Brain Res (1985) 60:335-49; and I. Madrazo et al, New Eng J Med (1987) 316:831-84. Although initial results with adrenal tissue and later with substantia nigra are encouraging, the mechanism and final outcome of this approach is unknown.
The ultimate cause of Parkinson's disease is still unknown. Infectious and environmental factors have been postulated, but no infectious agents have been isolated or environmental factors linked to the disease. There is no known hereditary predisposition. However, it is possible that the selective death of dopaminergic neurons in localized areas of the brain is due to the abnormally low concentration and/or synthesis of dopamine. This in turn may be caused by the absence or depletion of endogenous releasing factors, which may be responsible for synthesis and/or release of threshold concentrations of dopamine. Our discovery tends to support such a hypothesis.